6-fluoro steroids



United States Patent 3,438,978 6-FLUORO STEROIDS Howard J. Ringold,Albert Bowers, George Rosenkranz, and Octavio Mancera, Mexico City,Mexico, assignors, by mesne assignments, to Syntex Corporation, acorporation of Panama No Drawing. Filed Aug. 7, 1958, Ser. No. 753,629Claims priority, application Mexico, Aug. 9, 1957,

Int. Cl. C07c 169/ 18, 169/30, 169/34 U.S. Cl. 260-23955 79 Claims Thepresent invention relates to cyclopentanophenanthrene compounds and to aprocess for the preparation thereof.

More particularly the present invention relates to a novel process forthe production of 6-fiuoro steroids of the androstane and pregnaneseries by the reaction of a corresponding a,6a-oxido compounds withboron trifiuoride. The present invention also relates to certain novel60: -fluoro-A -androsten l7B-ol-3-one and esters thereof which may havean additional double bond between C-1 and C-2, and to a processproducing these compounds; these novel compounds are valuabletherapeutic agents and androgenic type hormones having, for example,decreased androgenic activity and increased anabolic activity and/ orincreased anti-estrogenic activity; owfluoro- A -androsten-17fl-ol-3-onewith or without an additional double bond between C1 and C-2 substitutedat C-17a by an alkyl, alkenyl or alkynyl hydrocarbon radical of lessthan 6 carbon atoms, such as, for example, methyl, ethyl, propyl, vinyl,ethinyl or propinyl and esters thereof and to a process for producingthese compounds; these novel compounds are valuable therapeutic agentshaving a high degree of lutinizing activity and a minimal androgenicactivity which is an undesirable side effect in progestational agents;6a-fiuoro-A -pregnen-3,20-diones and 6a-fiuoro-A-pregnen-17a-ol-3,20-diones with or without an additional double bondbetween C-1 and C-2 and esters thereof and to a process producing thesecompounds such as for example the novel 6u-fluoro-progesterone or6a-fiuoro-17a-acetoxy progesterone which are potent progestationalcompounds; in addition, some of the intermediates in producing thesecompounds such as for example the 6-fluor0 alkyl enol ethers as forexample the 6-fluoro 17a acetoxy progesterone ethyl enol ether arelikewise potent progestational compounds and exhibit a prolongedlutinizing action on the end organ; 6ot-fiuoro- A-pregnen-2l-ol-3,20-dione with or without a free or esterified17a-hydroxy group and esters thereof and to a process producing thesecompounds; these novel compounds are valuable intermediates andtherapeutic agents having progestational activity and no mineral cortoidactivity and being further useful in overcoming the mineral corticoidactivity of known compounds used for this purpose, such as for exampledesoxycorticosterone; in addition a double bond may be introducedbetween C-1 and C-2 by already known methods thereby increasing the saidtherapeutic value; 6u-fluoro-A -l7a,2l-diol-3,1l, 20-triones and thediesters thereof and to a process producing these compounds; these novelcompounds are valuable intermediates in producing 60: -fluoro corticalhormones, described in our U.S. application Ser. No. 740,550, filed June9, 1958, now U.S. Patent No. 2,934,546, an additional double bond may beintroduced between C-1 and C-2 thereby increasing the usefulness ofthese compounds as intermediates; these novel compounds also exhibit ananti-imfiammatory and thymolytic activity which makes them usefultherapeutic agents.

Although boron trifluoride or boron trifiuoride-etherate has been longknown in the art as an agent for opening a steroid epoxide ring, therehas been no indication that this compound will produce fluorosubstituents. Thus boron trifluoride is used in preparing 4-oxygenatedsteroids by the fission of 4,5-epoxides (U.S. Patent 2,842,571); Heusseret al. teaches the use of boron trifiuoride in preparing ll -ketocompounds from A' -oxido steroids (Helv. Chem. Acta. 34, 2106). In ourU.S. application Ser. No. 740,550, filed June 9, 1958, now U.S. PatentNo. 2,934,546, we described the preparation of 6u-fiuorosteroids byaddition of hydrogen fluoride to 5a-6a-OXidO cortical hormones. Althoughboron trifiuoride has been suggested as a catalyst in the opening of5oz,6a-oxido rings with hydrogen fluoride, when used in this way noadvantage has been found over the use of hydrogen fluoride alone.

In accordance with the present invention the surprising discovery hasbeen made that when boron trifluoride is reacted with a 5a,6a-oxidosteroid there is produced a stable Sa-hydroxy 6B-fluoro derivative. Inthis way the novel 6a-fiuoro and 6B-fluoro-A -3-keto steroids, morespecifically in the androstene or pregnene series may be prepared fromthe corresponding 5a,6a-oxido steroids having in the 3-position a ketogroup or a functionally modified keto group that can be converted into aketo group, such as for example an alkylendioxy substituent or free oresterified alcohol group by treating the 511,6- oxido compounds in anorganic solvent with boron triflnoride or boron trifiuoride-etherate orsimilar complex, isolating the Sa-hydroxy 6/3-fluoro compounds,regenerating the 3-keto function and dehydrating the fiuorohydrin withor without concurrent inversion of the 6-fiuoro atom. The last threesteps, namely regeneration of the 3-keto group, dehydration andinversion of the 6 3 to 60- fiuoro compounds may be carried out in onestep or separately as described in some detail below.

It will be readily seen that the present invention offers a greaterindustrial applicability since it does not involve handling of largeamounts of highly poisonous agent, prevents the corrosion of industrialequipment and offers a greater ease of material handling since borontrifluoride, especially in the form of its complex, such as for exampleetherate is a stable chemical compound having a boiling point above C.

The following formula serves to illustrate some of the novel compoundsof the present invention:

OR OR In the above formula the fluorine atom may be either in the alphaor the beta configuration and R refers to the same groups as previouslyset forth. R refers to a lower alkyl group of 6 carbon atoms or less.Typical examples of such a group are for example methyl, ethyl andpropyl. Y represents a double bond between C-1 and C-2 or a saturatedlinkage.

CHZR CHzR In the above formulas R, R and R refer to the same groups aspreviously set forth.

IQ fl? In the above formula F represents a fluorine atom both in the ,8and/or a configuration, Z represents two hydrogen atoms or a keto groupand R represents the same groups as previously set forth.

The novel process for making the compounds of the present invention maybe illustrated by the following equation:

I I I B F; I

'0" on F Thionyl H01 Chloride Acetic Acid H01 O Acetic Acid O l itAlthough in the above equation the 19-rnethyl group is indicated, thepresent process is also applicable to the 19-nor compounds. Further itwill be noted that the 6,8- fiuoro compounds are intermediates.

The fission of 5a,6a-0Xid0 steroids, more specifically of the androstaneor pregnane series with boron trifluoride or boron trifiuoride-etherateor a similar complex can be carried out in an organic solvent added insuch a proportion as to effect a dissolution of the steroid, andpreferably in an amount from 0.1 to 5 times the Weight of borontrifiuoride-etherate or an equivalent weight of boron trifluoride orsimilar complex.

As a solvent one can use organic solvents of low polarity, such asaliphatic or aromatic hydrocarbons, ethers, chlorinated or nitratedhydrocarbons either alone or in a mixture. Typical examples of suchsolvents of this type are hexane, benzene, diethylether, chloroform,nitromethane and tetrahydrofurane. The reaction can be carried out attemperatures from 20 C. to the boiling point of a solvent or solventmixture. In general, however, the reaction is best carried out attemperatures from 10 to 45 C. for maximum yields and satisfactoryreaction rates. We found also that the reaction time necessary forcarrying out the reaction may vary depending on the nature of thesteroid and the solvent used. Thus, for example3-cycloethyleneketal-5u,6a-oxido steroids were found to react fasterthan 3B-hydroxy-5a,6a-oxido steroids or their esters. The quantity ofboron trifiuoride used is preferably in excess of the stoichiometricquantity and in general 1 cc. of boron trifiuoride-etherate for each 1g. of steroid epoxide has been found satisfactory. The reaction isusually complete in a few hours and in practice a reaction period of 3to 24 hours has been used.

In practicing the first step above set forth the steroid is dissolved inthe solvent or solvent mixture and boron trifiuoride preferably in theform of its etherate or similar complex is then added while stirring.After a period of reaction as above set forth the resultant 5a-hydroxyfiuoro compound is separated and purified. It may be noted that in thefirst step the steroid starting material is a 3-ketone. As previouslyset forth compounds having in the 3 position a group convertible to a3-keto group may also be used as for example a 3-hydroxy or an acylated3- hydroxy group or a cycloethylene ketal group. In these instances the3-keto group must be or will be reconstituted prior to dehydration and/or inversion at C6. Thus, if the starting material is a 3-hydroxysteroid there is formed after the reaction with BF the corresponding3,5UL-dihY- droxy oli-fiuoro compound which is selectively oxidized by aconventional treatment with chromic acid. If there is present in thestarting material a 3-acyloxy group after the BF step the acyloxy groupof the product is first conventionally saponified as with alkali metalcarbonate, bicarbonate or methoxide and the 3-hydroxy group is thenoxidized. If the 3-substituent is a cycloethylene ketal group then thisgroup may be either treated with mild acid immediately after the firststep to regenerate the 3-keto radical or this may take place as a resultof any subsequent dehydration involving the use of acid.

The 3-keto-5oc-hydroxy-6B-fluoro products or their ketals as indicatedare then directly dehydrated with concomitant inversion of the6,8-fiuoro atom to 6m-fluoro atom. Such dehydration was preferablycarried out using anhydrous mineral acids and an organi acid as solvent;the temperature is not critical in this reaction and best yields wereobtained at temperatures from 5 to 20 C.; likewise, a reaction period of2 to 8 hours was found to give most satisfactory results. Typicalexamples 'of mineral acids of this type are dry hydrogen chloride andsulfuric acid and typical examples of organic acids are glacial aceticacid, propionic acid or butyric acid; i.e., lower aliphatic acids. Inpracticing the step above set forth the 5ahydroxy-6B-fluoro steroid forexample, is dissolved in glacial acetic acid and a stream of dryhydrogen is passed through the solution for 4 hours. After the reactionas above set forth, the resulting 6a-fiuoro-A -3-keto compound wasseparated and purified.

In the case where the 65-fluoro was the desired product theSwhYdlOXY-6B-flll010 compound was dissolved in a basic solvent as forexample pyridine, thionyl chloride was added and the temperature of thereaction mixture was kept preferably at below 0 C. Alternatively theprocess as above set forth was carried out using an alkali metalhydroxide as for example sodium hydroxide and an [alcohol as ethanol.

Isolation and purification produced a 6,8-fluoro-A -ketocompound whichwas then converted into 6a-fluoro-A -3- keto compound by treatment withdry hydrogen chloride in acetic acid as above set forth, followed byisolation and purification.

As may be understood the above reaction is applicable in general topregnane and androstane derivatives of the character set forth. However,in some instances as indicated in the following examples the samecompounds may be conveniently produced either directly or by preparingan androstane or pregnane intermediate differing in the side chain fromthe final compound and the side chain subsequently modified byconventional methods. Thus, for example 6wfluoroA -androsten-3,17-dionemay be an intermediate for the production of 6a-fluoro-testosterone andthe 6ot-fiuorotestosterone may also be prepared from3-ethylenedioxy-5oz,6a-oxido-androstan-1713-01.

The following specific examples serve to illustrate the presentinvention but are not intended to limit the same:

Example I stem-3,8,17p-diol, M.P. 158 0., [0. -63 (chloroform).

A solution of 3 g. of the above compound in 300 cc. of a mixture ofequal parts of ether and benzene was treated with 3 cc. of borontrifluoride etherate and kept for 3 hours at room temperature. Thesolution was then washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residue was purified bychromatography on neutral washed alumina, thus giving the 3,17-diacetateof 6B-fluoro-androstan-3,8,5a,17B-triol, M.P. 212-214 C., [OLJD 31(chloroform).

A mixture of 3.5 g. of this diacetate and a 0.2 normal solution ofperchloric acid in methanol was refluxed for 2 hours, cooled, dilutedwith water and the precipitate was collected, washed and dried undervacuum. The residue, consisting of the crudefl-fiuoro-androstan-3,l3,5m,17B-triol, was purified by crystallizationfrom acetoneiexane, thus giving the pure compound M.P. 208-209 C., [OLJDi0 (chloroform) A solution of 3 g. of the crude triol in 150 cc. ofacetone was cooled to 0 C. and treated with an 8 normal solution ofchromium trioxide which was prepared by mixing 1.6 g. of chromiumtrioxide with concentrated sulfuric acid and water. The reagent wasadded dropwise to the stirred solution in the course of approximately 2minutes, while the temperature was maintained below 0 C. The mixture wasstirred for half an hour at 0 C. and then diluted with water andextracted with ether. The extract was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. The residuecrystallized from ethyl acetate to give6fi-fluoro-androstan-5u-ol-3,17-dione, M.P. 227-228 C., [ab +113(chloroform).

2.5 g. of the above compound was dissolved in 30 cc. of pyridine, cooledto 0 C. and slowly mixed under stirring with 3 cc. of thionyl chloride,taking care that the temperature of the mixture did not rise over 0 C.The mixture was stirred for 2 hours further at 0 C. and then poured intoice water and extracted with ethyl acetate. The extract was washed withwater, dilute hydrochloric acid, 5% sodium carbonate solution and water,dried over anhydrous sodium sulfate, filtered and evaporated to dryness.The residue was chromatographed on neutral washed alumina, thus giving6,8-fiu'oro-A -androsten-3,17-dione, M.P. 141143 C., ultravioletabsorption, kmax, 234 m log E 4.10, [(11 +78 (chloroform).

2 g. of 6l8-fiuoro-A -androsten-3,17-dione was dissolved in 80 cc. oftetrahydrofurane and the solution was added dropwise to a stirredsuspension of 1.2 g. of lithium aluminum hydride in 40 cc. oftetrahydrofurane and the mixture was refluxed for 1 hour. The excess ofhydride was decomposed by the cautious addition of acetone and thensaturated sodium sulfate solution was added. The precipitate was removedby filtration and well washed with hot tetrahydrofurane and the combinedfiltrate and washings was evaporated to dryness under reduced pressure.The crude 6fi-fiuoro-A -androsten-3[3,17fl-diol thus obtained waspurified by crystallization from ethyl acetate.

2 g. of the above crude diol was dissolved in 200 cc. of chloroform,mixed with 20 g. of manganese dioxide and stirred for 24 hours at roomtemperature. The mixture was filtered and the solution was evaporated todryness. Recrystallization of the residue from acetone-hexane furnished6 3-fluoro-testosterone, M.P. 169171 C., ultra violet absorption A 234III/L, log E 4.09; [0:1 10.

1 g. of 6fi-fluoro-testosterone was dissolved in 50 cc. of acetic acidand a slow stream of dry hydrogen chloride was introduced into thesolution for 2 hours while the temperature of the mixture was kept below18 C. The mixture was poured into ice water and the precipitate wascollected, washed with water, dried and recrystallized fromacetone-hexane, thus furnishing 6ot-fluoro-testosterone, M.P. 156158 C.,ultraviolet absorption A 238 111,44, log E 4.17; [06113 +120(chloroform).

Example II 1 g. of 6,8-fluoro-androstan-5ot-ol-3,17-dione was treatedwith cc. of 1% methanolic potassium hydroxide for 5 minutes at roomtemperature and then neutralized with acetic acid, concentrated to asmall volume, poured into ice Water and extracted with ethyl acetate.The extract was washed with water, dried over anhydrous sodium sulfate,filtered and evaporated to dryness. The residue was purified bychromatography on neutral washed alumina to produce 6 8-fluoro-A-androsten-3,17-dione, identical to the one obtained in accordance withthe method of the previous example.

Example III Example IV A solution of 500 mg. of 6/3-fiuoro-A-androsten-3,17- dione in 50 cc. of methanol was cooled to C., and mixedwith 34 mg. of powdered sodium borohydride which was added in smallportions while the temperature was kept below 0 C. The mixture wasstirred for one hour further, then neutralized with a few drops ofacetic acid and diluted with water. The precipitate was collected byfiltration, washed, dried and recrystallized from acetone-hexane, thusgiving 6,8-fluoro-testosterone, identical to the one obtained inaccordance with the method of Example I.

Example V By the same method described in the previous example,6a-fiuoro-A -androsten-3,17-dione was converted into60t-flLlOI'O-tCStOStI'OH.

Example VI A mixture of 6 g. of testosterone, 110 cc. of anhydrousbenzene, 40 cc. of ethyleneglycol distilled over sodium hydroxide, and0.6 g. of p-toluenesulfonic acid was refluxed for 8 hours with the useof an adapter for the continuous removal of the water formed during thereaction. It was then cooled, sodium bicarbonate was added and theaqueous layer was separated, washed with water,

dried over anhydrous sodium sulfate and evaporated to dryness underreduced pressure. Crystallization of the residue from acetone-hexanegave 3-ethylenedioxy-A androsten-1713-ol.

A solution of 5 g. of the above compound in 100 cc.

of chloroform was cooled to 0 C. and mixed with an ether solution ofmonoperphthalic acid containing 1.2 mols of the reagent. The mixture waskept for 16 hours at room temperature in the dark and diluted withwater. The organic layer was separated, washed with water, sodiumbicarbonate solution and again with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. The residuecrystallized from acetone-hexane to give3-ethylenedioxy-5a,6a-oxido-androstan-1713-01.

Example VII By the same method as the previously example, 170:- methyland ethyl testosterones were converted into the corresponding 17a-alkyl3 GIhYlGHGdiOXY-Soc,6u-OXidO androstan-17/3-ols. The C21 acetates andpropionates of desoxycorticosterone gave the corresponding C21 ester of3-ethylenedioxy-5a,6a-oxidopregnan-21-ol-20-one; increasing the amountof reagents in the ketalization step, progesterone give3,20-bis-ethylenedioxy 50,6oc oxidopregnane and similarlydesoxycorticosterone gave 3,20-bisethylenedioxy-A -pregnen-2l-ol uponketalization. Acetylation and propionation of the hydroxyl group of thelatter compound by conventional methods, followed by epoxidation of thedouble bond afforded the corresponding C-21 ester of3,20-bis-ethylenedioxy-5u,6a-oxido-pregnan- 21-01.

A solution of 2 g. of the 21-acetate of cortisone in cc. of aceticanhydride was refluxed for 24 hours and then evaporated to dryness underreduced pressure. Crystallization of the crude product from methanolgave the 17,21-diacetate of cortisone. In another experiment the crudeproduct was purified by chromatography.

Subsequent ketalization and epoxidation, in accordance with Example VI,yielded the 17,21-diacetate of3-ethylenedioxy-5a,6a-oxido-pregnan-170,2l-di0l-11,20-dione.

Similarly, the 21-propionate of cortisone gave the 17-acetate-21-propionate of cortisone and then, upon ketalization andepoxidation, the 17-acetate-21-propionate of3-ethylenedioxy-5a,6a-oxido-pregnan 17a,21-diol-11,20- dione.

By the same method, 9a-chloro-cortisone and Qa-fiuOIO- cortisone werefirst converted into their 17,21-diacetates and finally into the17,21-diacetates of 9a-chloro-3-ethy1- enedioxy-Sa,6tx-oxido-pregnane17a,21 diol-11,20-dione and of9u-fluoro-3-ethylenedioxy-5ct,6a-oxidopregnane- 17a,21-diol-11,20-dione,respectively. The 21-propionates of 9a-chloro-cortisone and9a-fluoro-cortisone were converted into the 17-acetate-2l-pr0pionate of9a-chloro-3- ethylenediOXy-Sa,6a-oxido-pregnane 1711,21 diol-11,20-dione and of 9a-fluoro 3 ethylenedioxy-Su,6x-0xidopregnane-17a,2l-diol-11,20-dione, respectively.

By treatment of the 21-esters of Compound S, cortisone or its C-9ahalogenated analogues, with an acid anhydride which forms esters easilysaponifiable, such as trifiuoroacetic acid or the mixed anhydride offormic acid and acetic acid for example, there were obtained thecorresponding 17,21-diesters of such compounds, which in turn were firstketalized at C-3 and then epoxidized at 5, 6. For example, the2l-propionate of cortisone was converted into thel7-formate-2l-propionates of cortisone, of 3ethylenedioxy-A-pregnene-170:,21-di0l-11,20-dione and of 3ethylenedioxy-5u,6a-oxido-pregnane-17a-2l-diol-11, ZO-dione.

Example VIII A solution of 3 g. of3-ethylenedioxy-5a,6u-oxidoandrostan-l7 8-ol prepared in accordance withExample VI in 300 cc. of a mixture of equal parts of ether and benzenewas mixed with 3 cc. of boron trifluoride etherate, the mixture was keptovernight at room temperature and then diluted with water. The organiclayer was separated, washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated to dryness. The residue was purified bychromatography on neutral alumina to give 6fi-fluoro-3-ethylenedioxy-androstane-5a,17/3-di0l.

A solution of 2 g. of the above compound in cc. of acetone and 5 cc. ofwater was treated with 400 mg. of p-toluenesulfonic acid, the mixtureWas kept at room temperature for 6 hours and diluted with water. Theprecipitate formed was collected, washed with water and dried in vacuum.Recrystallization from acetone-hexane produced6/3-fiuoro-androstane-5a,17/3-diol-3-one.

1 g. of the previous compound was dissolved in 50 cc. of glacial aceticacid and a slow stream of dry hydrogen chloride was passed into thesolution for 4 hours while the temperature was kept below 20 C. Themixture was poured into ice water and the precipitate was collected,washed with water, dried and recrystallized from acetonehexane. Therewas thus obtained 6a-fiuoro-testosterone identical to that described inExample V.

Example IX In another experiment following the method of the previousexample, there was omitted the treatment with p-toluenesulfonic acid and6fi-fiuoro-3-ethylene-dioxyandrostane-5a,17,8-diol was directly treatedwith hydrogen chloride in acetic acid solution, by the method describedin the previous example for this reaction, to give 6u-fi11010-testosterone, identical to the final product obtained in Example V.

Example X By the same methods described in Examples VIII and IX, the17-acetate of 3-ethylenedioxy-5a,6a-oxido-androstan-17 3-ol (M.P. 184-5C. [111 88 (CHC1 was converted into the acetate of6u-fluoro-testosterone; the intermediate compounds are the 17-acetate of6fi-fiuoro-3- ethylenedioxy androstane 5a,17B-diol (M.P. 172164, 56(CHCl and of 6,8-fiuoro-androstane-a, 17B-diol-3-one, respectively.

Example XI By the same methods as described in Examples VIII and IX, thepropionate of 3-ethylenedioxy-5a,6a-oxidoandrostan-l7l8-ol was convertedinto the propionate of 6a-fiuoro-testosterone; the intermediatecompounds were the 17-propionates of6B-fluoro-3ethylenedioxy-androstane-5a,17B-diol and of6fi-fiuoro-androstane-5a,17(3-diol- 3-one.

Example XII When in the method of Example I the diacetate of Aandrostene-3B,17 8-dio1 was substituted by the acetate ofdhehydroepiandrosterone, there was obtained, in the epoxidation step,the acetate of 50:,6u-OXidO-Ztlldl05tfl1l-3/3- ol-17-one andfiuorination of this compound wilh boron triflouride gave the 3-acetateof 6,8fiuoro-androstane-3fl, 5m-diol-17-one. Saponification to the treediolone and oxidation with 1.1 equivalents of the oxidizing reagent ofchromium trioxide-aqueous sulfuric acid, furnished 6;?-fluoro-androstan-Sapl-B,17-dione, identical to the one obtained by themethod of Example I; for the saponification and oxidation, there werefollowed the method described in such example.

Example XIII A solution of 1 g. of the 3-acetate of 6S-fluoro-androstane-3 3,5a-diol-17-one, prepared in accordance with theprevious example, in 50 cc, of absolute benzene was mixed with 5 cc. of3 N solution of methyl magnesium bromide in absolute ether and refluxedfor 2 hours. The mixture was then poured into ice water, acidified withdilute hydrochloric acid and the reaction product Was extracted withethyl acetate. The extract was Washed with water to neutral and theorganic solvents were removed by distillation under vacuum. The residuecrystallized from acetonehexane to produce65-fiuoro-l7a-methyl-androstane-33,541, 17fl-tri0l.

1 g. of chromium trioxide was added in four portions to cc. of anhydrouspyridine, with stirring and keeping the temperature below 30 C. bycooling in ice. This oxidizing reagent of the chromic acid-pyridinecomplex was then mixed with a solution of l g. of6fi-fiuoro-l7amethyl-androstane-3 3,Su,17;3-triol, which was added understirring and keeping the temperature below 20 C. The mixture was keptstanding overnight at room temperature and then it was diluted withethyl acetate, filtered through Celite and the solution was washed withdilute hydrochloric acid and with water to neutral, dried over anhydroussodium sulfate and evaporated to drynesn under vacuum. There was thusobtained 6B-fiuoro-17a-methylandrostane-5oal7/3-diol in crude form.

This crude diol was dissolved in 100 cc. of 1% methanolic potassiumhydroxide and after 5 minutes at room temperature the mixture wasneutralized with acetic acid, diluted with water and extracted withether. The extract was washed with water to neutral, dried overanhydrous sodium sulfate, filtered and evaporated to dryness.Crystallization of the residue from acetone-hexane yielded6}3-fiuoro-l7u-methyl-testosterone.

10 Example XIV When in the method of the previous example methylmagnesium bromide was substituted by ethyl magnesium bromide, there wasobtained 6,6-fiuoro-17a-ethyl-testosterone.

Example XV When in the method of Example XIII, the methyl magnesiumbromide was substituted by acetylene magnesium bromide, there wasobtained Gfi-fluoro-17a-ethinyl-testosterone.

Example XVI In other experiments, the oxidation of the 6,8-fiuoro-17a-alkyl (ethynyl)-androstane-3,8,5a,17B-triols was carried out inacetone solution by reaction with 1.1 equivalents of chromium trioxidemixed wtih concentrated sulfuric acid and water, such as has beendescribed for this reaction in Example No. 1.

Example XVII A mixture of 2 g. of 6,8-fiuoro-A -androstene-3,17-dione,obtained in accordance with the method of Example No. 1, 50 cc. of drybenzene free of thiophene, 0.5 g. of pyridine hydrochloride, 4 cc. ofabsolute ethanol and 4 cc. of ethyl orthoformate was refluxed for 3hours and then 5 cc. of solvent was distilled; another 4 cc. of ethylorthoformate was added and the mixture was refluxed for 2 hours more.The solvents were removed by distillation under reduced pressure and theresidue was extracted with ether; the ether solution was washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization of the residue from acetonehexane furnishedGfi-fluoro-3ethoxy-A -androsta-dien- 17-one.

This enol ether was treated with methyl magnesium bromide by the methoddescribed for this reaction in Example XIII, and the product of thisGrignard reaction namely 6 8-fiuoro-17a-methyl-3ethoxy-A -androstadien-175-01, was dissolved in 50 cc. of acetone, acidified to pH 1 by theaddition of dilute hydrochloric acid (1:1), kept standing at roomtemperature for one hour and then diluted with water. The reactionproduct was extracted with ethyl acetate and the extract was washed withwater, 5% sodium carbonate solution and water, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Theresidue was crystallized from acetone-hexane, thus giving6a-fiuoro-17a-methyl-testosterone.

Example XVIII 1 g. of 6-fluoro-3-ethoxy-A -androstadien-17-one wasdissolved in cc. of a mixture of ether and benzene (1:1), mixed with 10mols of ethyl lithium in ether solution and kept for 48 hours undernitrogen. It was then poured into water and the organic layer wasseparated and washed with water, dried over anhydrous sodium sulfate andevaporated to dryness. The residue was dissolved in acetone and treatedwith hydrochloric acid in accordance with the method of the previousexample. There was thus obtained 6a-fiuoro-l7a-ethyl-testosterone.

Example XIX A solution of 1 g. of 6-fluoro-3-ethoxy-A -androstadien-17-one in 40 cc. of anhydrous benzene was added under nitrogen to acooled solution of 1 g. of potassium metal in 50 cc. of anhydroust-butanol which had also been prepared under nitrogen. A slow stream ofdry puri fied acetylene was introduced into the solution for 40 hours atroom temperature. The mixture was poured into 200 cc. of dilutehydrochloric acid, the organic solvents were removed by steamdistillation and the precipitate was filtered from the cooled mixture.Recrystallization from acetone-hexane yielded 6-fiuoro 17ozethynyl-3-ethoxy- A -androstadien17,8-01.

Hydrolysis of the ether group of the latter compound, as described forthis reaction in Example No. XVII af- 11 forded6t3-fluoro-17a-ethinyl-testosterone in crude form, which was purified byrecrystallization from acetonehexane.

Example XX Example XXI A mixture of 1 g. of 6 3-fluoro-testosterone, 10cc. of pyridine and 1 cc. of acetic anhydride was kept at roomtemperature for 4 hours and then poured into ice water, and extractedwith methylene dichloride. The extract was consecutively washed withwater, dilute hydrochloric acid, 5% sodium carbonate solution and water,dried over anhydrous sodium sulfate and evaporated to dryness.Crystallization from acetone furnished the acetate of 68-fiuoro-testosterone.

Example XXII When in the method of the previous example6fl-fluorotestosterone was substituted by 6a-fluoro-testosterone and theacetic anhydride was substituted by propionic anhydride, there wasobtained the propionate of 6a-fl1101'0- testosterone. Similarly, bytreatment with corresponding anhydrides or chlorides of hydrocarboncarboxylic acids having up to 12 carbon atoms, there were obtained thecorresponding esters of oa-fluoro-testosterone and ofGB-fluoro-testosterone. Specifically these were the enanthate,cyclopentylpropionate and benzoate.

Example XXIII When in the method of the previous example 6a-fiuorotestosterone was substituted by 6a-fiuoro-17a-ethynyl testosterone andthe more drastic conditions conventionally employed for esterificationof tertiary alcohols were used (reflux and acid conditions) there wereobtained the acetate, and cyclopentylpropionate of 6a-fiuoro-17a-ethynyltestosterone. In the same there was also made the 17-acetate,propionate, cyclopentylpropionate and benzoate of 17a-methy1 and17a-ethyl-6a-fluoro-testosterone.

Example XXIV By the process as described in the previous example therewas obtained the acetate and propionate of60afluoro-17a-viny1-testosterone.

Example XXV By the same methods as described in Examples 8 and 9, 17methyl-3-ethylenedioxy-5,8,65-oxido-androstan-175-01 was converted into17-methyl-6a-fiuoro-testosterone; the intermediate compounds were17a-methyl-6fi-fiuoro-3- ethylenedioxy-androstane5a,17fl-diol and17a-methyl-6B- fiuoro-androstane-5a,17fl-diol-3-one, respectively.

Example XXVI By the same methods as described in Examples Nos. 8 and 9,17a-ethyl-3-ethylenedioxy-5a,6a-oxido-androstan- 17B-ol was convertedinto 17a-methyl-6a-fiuoro-testosterone; the intermediate compounds were17a-ethyl-6flfluoro-3-ethy1enedioxy-androstane-Sa,17,8-dio1 and170sethyl-Gfi-fiuoro-androstane-5a,17/3-diol-3-one, respectively.

Example XXVII A solution of 5 g. of 17a-ethinyl-l9-nor-A -androstene-313,17fl-diol in 100 cc. of chloroform was treated with an ethersolution of monoperphthalic acid containing 1.2

molar equivalents of the reagent and the mixture was allowed to react atroom temperature in the dark for 20 hours. It was then diluted withwater, the organic layer was separated and washed with aqueous sodiumbicarbonate solution and water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. The residue was purifiedby chromatograhpy on neutral alumina to produce 17a-ethinyl-Sa,6-a-oxido-19-norandrostane 3fi,l7fi-diol.

3 g. of the above compound was dissolved in a mixture of 150 cc. ofether and 150 cc. of benzene, cooled to 0 C. and treated dropwise withstirring with 3 cc. of boron trifluoride etherate. After 3 hoursstanding at room temperature, the mixture was diluted with water and theorganic layer was washed with water, dried over anhydrous sodium sulfateand evaporated to dryness. Chromatographic purification of the residueon neutral alumina yielded 17a-ethinyl-6/3-fluoro-19-nor-androstane-3fi,5a,17fl-triol.

A solution of 2 g. of the above triol in cc. of acetone was cooled to 0C. and treated with 8 N solution of chromic acid prepared by mixingchromium trioxide, concentrated sulfuric acid and water; the reagent wasadded to the stirred solution kept at 0 C. under nitrogen, in the courseof approximately 3 minutes, until the yellow color of the mixturepersisted. The stirring was continued for a further 5 minutes at 0 C.and then the mixture was diluted with water and extracted with ether.The extract was washed with water, dried over anhydrous sodium sulfateand evaporated to dryness. Recrystallization of the residue from ethylacetate furnished 17aethinyl-6 3-fl-uoro-19-nor-androstane-5 a, 17fi-diol-3 -one.

1 g. of 17a-ethinyl-6fi-fiuoro-19-nor-androstane-5a,171idiol-3-one wasmixed with 50 cc. of glacial acetic acid and a slow stream of dryhydrogen chloride was introduced into the mixture for 2 hours while thetemperature was kept below 18 C. The mixture was poured into water andthe precipitate formed was collected by filtration, washed with water,dried and recrystallized from acetonehexane, thus giving17a-ethinyl-6a-fluoro-19-nor-testosterone.

Example XXVIII A mixture of 2 g. of 17a-methyl-6ot-fiuoro-testosterone,100 cc. of anhydrous tertiary butanol, 0.8 g. of selenium dioxide and0.5 cc. of pyridine was refluxed for 72 hours under an atmosphere ofnitrogen, cooled, filtered through Celite, Washing the filter with hott-butanol, and the combined filtrate and washings was evaporated todryness under reduced pressure. The residue was disolved in acetone,treated with recolorizing charcoal, dried over anhydrous sodium sulfateand evaporated to dryness; the residue was purified by chromatography onneutral alumina. There was thus obtained I7'a-In6thYl-6a-fll10l0- A-androstadien 17/3-ol-3-one. In the same way starting with 17-acetateand propionate of 17wmethyl-6a-fluorotestosterone there was obtained thecorresponding A compounds.

Example XXIX By the method of the previous example, 17u-ethynyl-6u-fiuoro-testosterone was converted into 17u-ethynyl- A-6a-fluoro-androstadien-17fi-ol-3-one.

Example XXX By the method of Example No. 28,17a-vinyl-6a-fluorotestosterone was converted into 17u-vinyl-6u-fluoro-Aandrostadien-17fi-ol-3-one.

Example XXXI 5 g. of the acetate of A pregnen-3 3-ol-20-one was treatedwith monoperphthalic acid and the product was worked up by the methoddescribed in Example No. 1. There was thus obtained the acetate of5a,6a-OXidO pregnan-3fl-ol-20-one, M.P. 168-169, [001 +9 (chloroform).

Following the method described in Example I boron trifluoride etheratefission of the above u,6a-oxido compounds produced the 3-acetate of6B-fluoro-pregnane-3/3, 5a-diol-20-one, MP. 223224 C. [a] =42(chloroform); hydrolysis of the acetyl group of the latter compound gavethe free 6B-fiuoro-pregnane-3[3,5u-diol-20- one, and oxidation of thehydroxyl group at C-3 furnished 6fi-fluoro-pregnan-5a-ol-3,20-dione,M.P. 274-278 C., [a] =8l (pyridine).

The diolone was dehydrated by the reactions described in Examples I andII and the dehydration product was worked up in the form indicated; thedehydration by means of thionyl chloride or methanolic potassiumhydroxide yielded 6,8-fluoro-progesterone, "MP. 156-158, ultravioletabsorption: A max. 234 my, log E 4.12; the dehydration by treatment withdry hydrogen chloride produced 6a-fluoro-progesterone, M.P. 146-80, Amax. 236 m log E 4.19, [@1 +191 (chloroform).

Example XXXII By the same methods described in Examples VIII and IX,3,20-bisethylenedioxy-5a,6a-oxido-pregnane was converted into6a-fiuoro-progesterone (M.P. l468 (3., identical to that described inExample XXXI); the intermediate compounds wereGB-fluoro-B,ZO-bisethylenedioxy-pregnan-5a-ol and6fi-fluoro-pregnan-5a-ol-3,20- dione, respectively.

Example XXXIII When in the method of Example XXXI the acetate of A-pregnen-3flol-20-one was substituted by the 3,17- diacetate of A-pregnene-3/3,l7a-diol-20-one, there was obtained as final product theacetate of 60z-fl11O1O-l7othydroxy-progesterone, or of its 6l8-isomer,respectively.

Example XXXIV When in the method of Example XXXI, the diacetate of A-pregnene-3/3,17a-diol-20-one was substituted by a mixed diester of thiscompound, whose acyloxy group at C-l7 was the propionate and caproate,there was obtained the corresponding ester of6u-fluoro-17u-hydroxyprogesterone or of its 6,8-isomer. Thus, weobtained from the corresponding 3-acetate-17-acylate of A -pregnene-3,8,17u-dl01-20-OI16 the propionate and the caproate of the6-fiuoro17a-hydroxy-progesterone.

Example XXXV By the same methods as described in Examples VIII and IX,17-acetate of 3-ethylenedioxy-5a, 6a-oxido-pregnan-17a-ol-20-one wasconverted into the l7-acetate of 6wfluoro-l7a-hydroxy-progesterone (M.P.249-51 C., [111 +55 (CHCl the intermediate compounds were thel7-acetates of 6 8-fiuoro-3-ethylenedioXy-pregnane- 5a,17a-diol-20-oneand of 6fl-fluoro-pregnane-5a,17adiol-3,20-dione, respectively.

Example XXXVI By the same methods as described in Examples Nos. VIII andIX, l7-caproate of 3-ethylenedioxy-5a,6a-oxidopregnan-l7a-ol-20-one wasconverted into the l7-caproate of 6a-fluoro-17a-hydroxy-progesterone;the intermediate compounds were the 17-caproates of6fl-fluoro-3-ethylenedioxy-pregnane-5a,17a-diol-20-one and of6fi-fiuoro-preg- 11211'16-5cc,17oc-diOl-200I16 and of6fi-fiuoro-pregnane-5a, l7a-diol-3,20-dione, respectively.

Example XXXV II A mixture of 5 g. of the B-acetate of A-pregnene-3B,l7adiol-20-one, 300 cc. of anhydrous benzene, 35 cc. ofethylene glycol and 250 mg. of p-toluenesulfonic acid was refluxed for12 hours with the use of an adapter for the continuous removal of theWater formed during the reaction. There was then added 50 cc. of a 2 Nsolution of sodium carbonate and 200 cc. of water and the benzene layerwas separated, washed with water, dried over anhydrous so- 14 diumsulfate and evaporated to dryness under reduced pressure. There was thusobtained the S-acetate of 20- ethylenedioxy-A -pregnene 35,1711 -diol incrude form,

' which was used for the next step without further purification. Inanother experiment the pure substance was obtained by severalrecrystallizations from acetone-hexane.

A cooled solution of 5 g. of the crude 3-acetate of 20- ethylenedioxy-A-pregnene-3[3,17a-diol in cc. of chloroform was mixed with an ethersolution of monoperphthalic acid containing 1.2 mols of the peracid andthe mixture was allowed to stand at 05 C. overnight in the dark; it wasthen mixed with water and the organic layer was separated and washedwith Water, dried over anhydrous sodium sulfate and evaporated todryness. The residue was chromatographed on neutral alumina, thusyielding the 3-acetate of ZO-ethylenediOxy-Su,6u-oxido-pregnane-3,B,17x-diol.

A solution of 3 g. of the above compound in a mixture of equal parts ofether and benzene was cooled in 0 C. and mixed with 3 cc. of borontrifluoride etherate. After 3 hours standing at room temperature it wasdiluted with water and the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, filtered and evaporated todryness. Chromatography of the residue on neutral alumina furnished the3-acetate of Gfl-fiuoro-ZO- ethylenedioxy-pregnane-3;3,5a,l7a-triol.

500 mg. of lithium aluminum hydride was added to a solution of 1 g. ofthe 3-acetate of 6,8-fluoro-20-ethylene dioxy-pregnane-3fi,5a,l7a-triolin 50 cc. of tetrahydrofurane and refluxed for 1 hour. After cooling,the excess of hydride was decomposed by the cautious addition of ethylacetate and then saturated aqueous sodium sulfate solution was added,followed by anhydrous sodium sulfate. The inorganic precipitate wasremoved by filtration and the filtrate was evaporated to dryness underreduced pressure. There was thus obtained6l3-fluoro-20-ethylenedioxy-pregnane-3B,5u,l7a-triol in crude form; inanother experiment the pure substance was prepared by recrystallizationfrom acet0nehexane.

A solution of 800 mg. of chromium trioxide in a mixture of 3 cc. ofpyridine and 1 cc. of water was added to a solution of the above crudetriol in 10 cc. of pyridine previously cooled at 0 C. The mixture waskept standing overnight at room temperature and then diluted with 50 cc.of ethyl acetate and filtered through Celite, washing the filter with alittle ethyl acetate. The combined filtrate and washings was washedseveral times with saturated aqueous sodium chloride solution, driedover anhydrous sodium sulfate, filtered and evaporated to dryness.Crystallization of the residue of from acetone-hexane attorded6/3-fluoro-20-ethylenedioxy-pregnane-Sor,l7a-diol-3-0ne.

A slow stream of dry hydrogen chloride was introduced for 3 hours into asuspension of 1 g. of the above compound in 15 cc. of glacial aceticacid, maintaining the temperature below 20 C. After pouring into waterthe precipitate was collected by filtration and recrystallized fromacetone-hexane, thus yielding 60t-flllO1'O-170L-hydI'OXYpI'O- gesterone.

Example XXXVIII A mixture of l g. of the crude 6fl-fiuoro-20-ethylene-(liOXy-3fi,5oc,l7oc-diOl, described in the previous example, 50 cc. ofacetone containing 1 cc. of water and 100 mg. of p-toluenesulfonic acidwas kept for 6 hours at room temperature and then diluted with water.The precipitate was collected, washed with water and dried under vacuum.There was thus obtained 6fifluoro-pregnane-3fi,5a,17atriol in crudeform. The pure substance was obtained in another experiment byrecrystallization from methanol.

800 mg. of the above crude triolone dissolved in 8 cc. of pyridine wastreated with a solution of 660 mg. of chromium trioxide in 2.4 cc. ofpyridine and 0.8 cc. of water, such as has been described in thisoxidation in the previous example, to produce6fi-fiuoro-pregnane-5a,17adiol-3,20-dione.

The conversion of the above compound into 6OL-fill0l'0-17a-hydroxy-progesterone was carried out as described in Example XXXVII.

Example XXXIX In another experiment, 1 g. of the crude 3-acetate of 20CthYlCHBdlOXY-Sa,60z-OXldO-pr6gI1anC-3,8,17x-dl0l, obtained inaccordance with Example XXXVII, was refluxed in 50 cc. of 1% methanolicpotassium hydroxide in order to saponify the ester group at C3; by thesame method as described in Example No. XXXVII, there was then carriedout the reaction with boron trifluoride etherate to produce6,8-fluoro-20-ethylenedioxy-pregnane-3 [3,5 a, 17 a-triol, identicalwith the intermediate described in such example.

Example XL A mixture of 5 g. of 17a-hydroxyprogesterone, 300 cc. ofanhydrous benzene, 35 cc. of ethyleneglycol and 250 mg. ofp-toluenesulfonic acid was refluxed for 12 hours with the use of anadapter for the continuous removal of the water formed during thereaction and then cooled and treated with 50 cc. of 2 N aqueous sodiumcarbonate solution and 500 cc. of water. The benzene layer was separatedand washed with water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. There was thus obtainedthe crude 3,20-bis-ethylene-dioxy-A -pregnen-l7a-ol.

A cooled solution of 5 g. of the above crude ketal in 10 cc. ofchloroform was mixed with an ether solution of monoperphthalic acidcontaining 1.2 molar equivalents of the reagent and the mixture was keptfor 16 hours at a temperature of C., in the dark, and then diluted withwater. The organic layer was separated, washed with water, dried overanhydrous sodium sulfate, filtered and evaporated to dryness.Chromatography of the residue on neutral alumina yielded3,2(l-bis-ethylenedioxy 506,611- oxido-pregnan-lh-ol.

A solution of 3 g. of the above compound in a mixture of 150 cc. ofether and 150 cc. of benzene was cooled to 0 C., mixed with 3 cc. ofboron trifluoride etherate and kpet standing at room temperature for 3hours. It was then diluted with water and the organic phase was driedover anhydrous sodium sulfate, filtered and evaporated to dryness. Theresidue was purified by chromatography on neutral alumina, thus giving 63-fluoro-3,20-bisethylenedioxy-pregnane-Sa, 17(X-di01.

A slow stream of dry hydrogen chloride was introduced for 3 hours into asolution of 2 g. of the above compound in 100 cc. of glacial aceticacid, while the temperature was maintained below 18 C.; it was thenpoured into water and the precipitate was collected by filtration,washed with water, dried and recrystallized from acetone-hexane. Therewas thus produced Ga-fluoro-17a-hydroxyprogesterone identical to thatdescribed in Example XXXVII.

Example XLI 800 mg. of p-toluenesulfonic acid was added to a solution of5 g. of 6fi-fluoro-3,20-bis-ethylenedioxy-pregnane- 5a,17a-diol-preparedin accordance with the previous example in 300 cc. of acetone and themixture was allowed to stand for 6 hours at room temperature. Afterdiluting with water the precipitate was collected by filtration, washed,dried under vacuum and recrystallized from acetone-hexane, thusfurnishing 6l3-fluoro-pregnane-5a, 17u-di0l-3,20-dione.

3 cc. of thionyl chloride was slowly added to a stirred solution of 2.5g. of 6fl-fiuoro-pregnane-5a,17ot-diol-3,20- dione in 30 cc. ofpyridine, maintaining the temperature of the mixture at 0 C. Thestirring was continued for 2 hours further at 0 C. and the mixture wasthen poured into ice water and the reaction product was extracted withseveral portions of ethyl acetate. The extract was washed with Water,dilute hydrochloric acid, 5% sodium carbonate solution and water, driedover anhydrous sodium sulfate, filtered and evaporated to dryness.Chromatography of the residue on neutral alumina afforded 6 8-fluoro-17u-hydroxyprogesterone.

Following exactly the method described in Example No. XL, there wasinverted the steric configuration of 613-fluoro-17a-hydroxyprogesteroneby treatment with dry hydrogen chloride in acetic acid solution andfiat-1111010- 17a-hydroxyprogesterone was obtained after isolation andpurification.

Example XLII A mixture of 6B-fluoro-pregnane-5a,17a-diol-3,20dione andcc. of 1% methanolic potassium hydroxide was stirred for 5 minutes atroom temperature, acidified with acetic acid, concentrated to a smallvolume, diluted with ice water and extracted with ethyl acetate. Theproduct was then worked up as described in the previous example, to give6fl-fluoro-17u-hydroxyprogesterone, identical with the one obtained inaccordance with the previous example.

Example XLIII In another experiment, 2 g. of 6 3-fluoro-pregnane-5a,17oc-dl0l-3,20-dl0116, obtained in accordance with Example No. XLI wastreated in glacial acetic acid solution with dry hydrogen chloride ashas been described in Example No. XL, thus producing6a-fluoro-17a-hydroxyprogesterone, identical with the one obtained inaccordance with that example.

Example XLIV A mixture of 2 g. of 6oc-fi11OIO-17 u-hydroxyprogesterone,10 cc. of acetic anhydride and 200 mg. of p-toluenesulfonic acid wasstirred for 12 hours at room temperature and then poured into water. Themixture was heated for half an hour on the steam bath and cooled and theprecipitate formed was collected, washed with water and dried. There wasthus obtained the crude diacetate of 6-fluoro-Apregnadiene-3,17-diol-20-one. In another experiment the product waspurified by chromatography on neutral alumina.

The above crude 3-enol-acetate-17-acetate was dissolved in 100 cc. of 1%methanolic potassium hydroxide, cooled to 5-10 C. and allowed to standat this temperature for 1 hour; it was then neutralized with aceticacid, concentrated to a small volume, diluted with water and theprecipitate was collected, washed with water, dried and recrystallizedfrom acetone-hexane. There was thus obtained the acetate of6a-fluoro-l7a-hydroxyprogesterone, identical with that obtained inExample No. XXXIII.

Example XLV By the same method as described in the previous examples, 1g. of 6/8-fluoro-17u-hydroxyprogesterone was treated with 12 cc. ofpropionic anhydride and 200 mg. of p-toluenesulfonic acid, to producethe dipropionate of 6-fluoro-A -pregnadiene-3,17a-diol-20-one and thenthe enol-ether group of this compound was hydrolyzed to form thepropionate of 6a-fluoro-17a-hydroxy-progesterone.

Example XLVI A mixture of 1 g. of 6a-fluoro-17a-hydroxyprogesterone, 50cc. of anhydrous benzene, 5 g. of caproic anhydride and 400 mg. ofp-toluenesulfonic acid was allowed to stand at room tempreature for 3days and then poured into water. The organic layer was separated andwashed with aqueous sodium bicarbonate solution and water, dried overanhydrous sodium sulfate and evaporated to dryness. The residue wastreated with methanolic potassium hydroxide, as described in theprevious example, and the product was recrystallized fromacetone-hexane. There was thus obtained the 17-caproate of6ot-fiuoro-17w hydroxyprogesterone.

1 7 Example XLVII Applying the method of Example XXVIII,Got-fluoroprogesterone was converted into 6a-fluoro-Apregnadiene-3,-20-dione.

Example XLVIII By dehydrogenation ofGot-fluoro-l7a-hydroxy-progeste-rone 17-acetate, in accordance with[Example No. XXVIII, there was obtained '6a-fluoro-A-pregnadienl7a-ol-3,20-dione 17-acetate.

Example XLIX By an analogous method to that described in Example XXVIH,17u-propyl-6a-fluoro-testosterone 17-propionate was converted intol7a-propyl-6a-fluoro-A -androstadien- 17fi-ol-3-one 17-propionate.

Example L A mixture of 5 g. of 21-fluoro-l7a-acetoxy-progesterone, 100cc. of anhydrous benzene, 35 cc. of ethyleneglycol distilled over sodiumhydroxide and 600 mg. of ptoluenesulfonic acid was refluxed for 8 hourswith the use of an adapter for the continuous removal of the waterformed during the reaction. Sodium bicarbonate solution was added to thecooled mixture and the organic layer was separated and washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness.The residue crystallized from acetone-hexane to yield2l-fluoro-l7uacetoxy-3-ethylene-dioxy-A -pregnen-2O-one.

4 g. of the above compound was dissolved in 80 cc. of chloroform, cooledto C. and mixed with an ether solution of monoperphthalic acidcontaining 1.2 molar equivalents of the reagent. The mixture was kept inthe dark for 16 hours at a temperature between 0 and 5 C. and thendiluted with water. The organic layer was washed with aqueous sodiumbicarbonate solution and then with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. Thresiduecrystallized from acetone-hexane to give 21-fluoro-17ot-acetoxy-3-ethylenedioxy-5m,Ga-pregnan-ZO-One.

To a solution of 3 g. of the above compound in 300 cc. of a mixture ofequal parts of ether and benzene there was added 3 cc. of borontrifluoride etherate and the mixture was kept standing at roomtemperature for 3 hours. After diluting with water the organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate andevaporated. Chromatography of the residue on neutral alumina aflorded65,2l-difluoro-l7a-acetoxy-3- ethylenedioxy-pregnan-Sa-ol-20-one.

2 g. of the above compound was dissolved in 150 cc. of acetone, mixedwith 3 cc. of water and 4-00 mg. of ptoluenesulfonic acid monohydrateand the mixture was kept at room temperature for 6 hours and dilutedwith water. The precipitate was filtered, washed with water and dried,thus giving 613,2l-difiuoro17u-acetoxypfgllaIJ-50L-O1-3,20diOI16 incrude form. In another experiment the pure compound was obtained byrecrystallization from acetone-hexane.

A solution of the above crude compound in 100 cc. of acetic acid wastreated with 2 cc. of concentrated hydrochloric acid and the mixture waskept at room temperature for 1 /2 hours. After diluting with water theprecipitate formed was collected, washed with water, dried andrecrystallized from acetone-hexane. There was thus obtained613,21-difluoro-17a-acetoxy-progesterone.

1.5 g. of 6fi,2l-difluoro-l7a-acetoxy-progesterone was dissolved in 75cc. of glacial acetic acid and a snow stream of dry hydrogen chloridewas introduced into the solution for 4 hours, maintaining thetemperature below 15 C. It was then poured into ice water and theprecipitate was filtered, washed with water, dried and recrystallizedfrom acetone-hexane. There was thus obtained 6m,21-difluoro-17a-acetoxy-progesterone.

18 Example LI In another experiment 2 g. of65,21-difluoro-17m-acetoxy-3-ethylene-dioxy-pregnan-5u-ol-20-one,intermediate compound in the previous example, was treated with dryhydrogen chloride in glacial acetic acid solution such as has beendescribed in such example, to produce in this manner directly6a,21-difluoro-17u-acetoxy-progesterone.

Example LH Example LIII 1.0 g. of 601,21-difluoro-17a.-acetoxyprogesterone was treated with ethyl orthoformate to produce6,2l-difluoro- 17a-acetoxy-3ethoxy-A -pregnadiene-20 one; similarly,6fi,2l-difluoro1Ian-propionoxy-progresterone was converted into6,21-difluoro-l7arpropionoxy-3-propoxy-A pregnadiene-ZO-one by reactionwith propyl orthoformate.

Example LIV A mixture of 2 g. of6a,2.1-difiuoro-17ot-acetoxyprogesterone, cc. of t-butanol, 0.8 g. ofselenium dioxide and 0.4 cc. of pyridine was refluxed under anatmosphere of nitrogen for 48 hours and then filtered through Celite,washing the filter with hot t-butanol. The combined filtrate andwashings was evaporated to dryness and the residue was treated withdecolorizing charcoal in acetone solution under reflux for one hour. Thesolution was filtered through Celite and the solvent was evaporated.Chromatographic purification of the residue on neutral alumina furnished6a,21-difluoro-17u-acetoxy- A -pregnadiene-3,2O-dione.

Example LV By the same methods described in Examples VIII and 1X,ZI-acetate of 3-ethylenedioxy-5u.,oot-oxido-pregnan- 21-ol-20-oneprepared from A -pregnan-2l-ol-3,20dione- 2l-acetate as described in thesaid example was converted into the 21-acetate of6wfluoro-desoxycorticosterone; the intermediate compounds were the21-acetates of 6-fi-fluoro- 3ethylenedioxy-pregnane-50,2l-diol-20-oneand of 613- fluoro-pregnane-5m,2l-diol-3,20-dione, respectively.

Example LVI By the same methods as described for the above example,21-propionate of 3,20-biS-filihY16l16diOXy-5oc,6ozoxido-pregnan-21-olwas converted into the 21-propionate of6oc-flllOIO-dCSOXYCOItlCOS'CCI'OHB; the intermediate compounds were the21-propionates of 6cc-flt1OIO-3,20bi$- ethylenedioxy-pregnane-S(1,2l-diol and of 6/3-fluoropregnane-5oc,2l-diol-3,20-dione, respectively.

Example LVII By the same methods as described in Examples VIII and 1X,17,2l-diacetate of3-ethy1enedioxy-5a,6tx-oxidopregnane-l7u,2l-diol-20-one (M.P. 186-8 C.,[a1 -78 (C-HCl prepared from A -pregnane-17,2l-diol- 3,20-dionediacetate was converted into the 17,2l-diacetate of oot-fiuoro-A-pregnene-l7a,2l-diol-3,20-dione (M.P. 2412, [:11 +53, Amax. 236 My, logE 4.17), the intermediate compounds were the 17,21-diacetates of 6,8-fiuoro-3-ethylenedioxy pregnane-5u.,'17ot,21-triol-20-one and of65-fluoro-pregnane-5a,17a-2l-triol-3,20-dione, respectively.

1 9 Example LVIII By the same methods as described in Examples VIII andIX, 17,2l-diacetate of3-ethylenedioxy-5u,6a-oxidopregnane-17a,21-diol-11,20-dione preparedfrom A pregnen-17a.,21-diol-3,l1,20-trione was converted into the17,2,l-diacetate of 60c-fi11OIO-COItiSOI1e by boron trifluoride fissionof the 50c,60z.-6POXld8 and subsequent preparative methods as above setforth; the intermediate compounds were the 17,21-diacetates of6oz-flLlOIO-3-6thYle116diOXY- regnane-Sa,l7a-21-triol-l1,20-dione and of6oc-flll01'0- regnane-Sa,17a,21-triol-3,l l,20-trione, respectively.

Example LVIX By the same methods as described in the previous eX- ample17,21-diacetate of 9a-chlor0-3-ethylenedioxy-5a,6a-oxido-pregnane-17a,2l-diol-11,20-dione was converted into the17,21-diacetate of 6a-fiuoro-9a-chloro-cortisone; the intermediatecompounds were the 17,21-diacetates of 6 3 fiUOIO-Qa chloro3-ethylenedioxy-pregnane-Sa,17a- 2l-triol-11,20-dione and of6fl-fluoro-9a-chloro-pregnanea,17a,21-triO1-3,l 1,20-trione,respectively.

Example LX By the same methods as above set forth in Example LVIX17,21-diacetate of 9a-fiuoro-3-ethylenedioxy-5a,6aoxido-pregnane-17a,2l-diol 11,20 dione was converted into the 17,2l-diacetate of6a,9a-difiuoro-cortisone; the intermediate compounds were the17,2l-diacetates of 6p, 9a-difiuoro-3 ethylenedioxy-pregnane5oz,17oc,2lt1i0l 11,20-dione and of 6B,9a-difiuoro-pregnane 5a,17oc,21-trio1-3,l1,20-trione, respectively.

Example LXI A mixture of 1 g. of the 21-acetate of6a-fluoro-desoxycorticosterone prepared in accordance with Example LV,and cc. of anhydrous methanol was mixed with a methanol solution ofsodium .methoxide, prepared by dissolving 70 mg. of sodium metal inabsolute methanol, and the mixture was stirred for 1 hour at 0 C. andunder an atmosphere of nitrogen. After acidifying with a few drops ofacetic acid the mixture was diluted with water and the precipitate wascollected, dried and recrystallized from acetone-hexane, thus giving thefree 6a-fluorodesoxycorticosterone.

A mixture of 500 mg. of 6a-fluoro desoxycorticosterone, 5 cc. ofanhydrous pyridine and 0.6 cc. of propionic anhydride was kept standingovernight at room temperature and then poured into water. The mixturewas heated for half an hour on the steam bath, cooled and theprecipitate was collected, washed with water, dried and recrystallizedfrom acetone-hexane, thus yielding the 21-propionate of6e-fluoro-desoxycorticosterone.

Example LXII By the same method as described in Example XXVIII6a-fluoro-testosterone acetate and 6/3-fiuoro-testosterone wereconverted into the corresponding A compounds by oxidation with seleniumdioxide.

Example LXIV By the same method as described in the above example thecyclopentylpropionates of 6e-fluoro-testosterone and6fi-fiuoro-testosterone were converted into the corresponding Acompounds.

20 Example LXV Example LXVI By the same method as described in theprevious example 6 /i-fiuoro-progesterone was converted into the same3-ethyl enol ether of 6-fiuoro-progesterone.

Example LXVII By the same method as described Example LXV the 17-acetateand caproate of 6a-fluoro-A -pregnen-l7a-ol-3, 20-dione were convertedinto the corresponding 3-ethyl enol ethers.

Example LXVIII By the same method as above substituting the ethyl orthoformate for propyl ortho formate there were obtained the 17 acetate andpropionate of 3-propoxy- A -pregnadien-17a-Ol-20-One 6-fiuoroderivative.

We claim:

1. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6a-fiuoro-testosterone.

3. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms.

4. A compound of the following formula:

0 R ""CH=CHR wherein R is selected from the group consisting of hydrogenand a hydrocarbon carboxylic acyl group of less than 12 carbon atoms, Ris a lower alkyl group and Y is se- 21 lected from the group consistingof a double bond between C-l and C-2 and a saturated linkage between C-1and -2.

5. fiat-fluoro-17a-vinyl-A -androsten-17p-ol-3-one.

6. The hydrocarbon carboxylic acid esters of less than 12 carbon atomsof 6a-fluoro-l7a-lower a1kenyl-A -androsten-17B-ol-3-one.

7. (Ea-fluoro-17a-vinyl-A -androstadien- 17p-ol-3-one.

8. The hydrocarbon carboxylic acid esters of less than 12-carbon atomsof 6a-fil1OI0-17a-10We1' alkeny1-A -androstadien-175-ol-3-one.

9. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms, R is alower alkyl group and Y is se lected from the group consisting of adouble bond between C-1 and C-2 and a saturated linkage between (3-1 and0-2.

11. A compound of the following formula:

CHzR

wherein R is fluorine and Y is selected from the group consisting of adouble bond between C-l and C-2 and a saturated linkage between C-1 andC-2.

14. A compound of the following formula:

CHzR

wherein R is fluorine and Y is selected from the group consisting of adouble bond between C-1 and (3-2 and a saturated linkage between C l andC-2.

15. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms, and R isselected from the group consisting of hydrogen and fluorine, and when Ris hydrogen, R is other than hydrogen.

20. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms, and R isfluorine.

21. 611,21difluoro-A -pregnadien-17a-ol-3,QO-dione. 22. The hydrocarboncarboxylic acid esters of less than 1-2 carbon atoms of6u,2-l-difluoro-A -pregnadien-l7ao1-3,20-dione.

23 23. A compound of the following formula:

CH R

wherein R is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acyl group of less than 12 carbon atoms, and R isfluorine.

24. A compound of the following formula:

GHzR

wherein R represents lower alkyl and R is selected from the groupconsisting of hydrogen and fluorine.

25. 6-fiuoro-3-lower alkoxy-A -pregnadien-20-one.

26. 6,21 difluoro-3-lower alkoxy-A -pregnadien-20- one.

27. A compound of the following formula:

CHzR

wherein R represents lower alkyl, R is selected from the groupconsisting of hydrogen and fluorine and R is selected from the groupconsisting of hydrogen and a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms.

28. A process for the production of 6-fluoro steroids selected from thegroup consisting of compounds of the pregnane series and compounds ofthe androstane series comprising reacting a corresponding 5a,6a-oxidocompound with boron trifluoride.

29. The process of claim 28 wherein the boron trifluoride is in the formof its etherate.

30. A process for the production of 6ot-fluoro-A steroids selected fromthe group consisting of compounds of the pregnane series and compoundsof the androstane series comprising reacting a corresponding5a,6oL-OXld0 compound with boron trifluoride to form the corresponding5ot-hydroxy-65-fiuoro-steroid and thereafter dehydrating and invertingsaid last mentioned steroid with a mineral acid.

24 31. 6-fluoro-175-hydroxy-17a-alkynl-4-androsten-3-ones of thefollowing formula:

-CECR3 wherein R is selected from the group consisting of methyl andhydrogen, R is selected from the group consisting of hydrogen and theacyl radical of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive, and R is selected from the groupconsisting of hydrogen and an alkyl radical containing from one to fourcarbon atoms, inclusive.

32. 6 fluoro -hydroxy-17a-ethinyl-4-androsten-3- one.

33. 6 fluoro 175-hydroxy-l7u-ethinyl-4-androsten-3- one 17-acylates inwhich the acyl radical is that of a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive.

34. 60c fluoro 175-hydroxy-17a-ethinyl-4-androsten- 3-one.

35. 65 fluoro 175-hydroxy-17u-ethinyl-4-androsten- 3-one.

36. 60c fluoro-175-hydroxy-17a-ethinyl-4-androsten-3- one 17-acetate.

37. 3 oxygenated 6 fluoro-5,175-dihydroxy-17ualkinyl androstanes of thefollowing formula:

a on. R j

wherein R is selected from the group consisting of methyl and hydrogen,and R is selected from the group consisting of hydrogen and an alkylradical containing from one to four carbon atoms, inclusive.

41. 35,175 dihydroxy-17a-ethinyl-5ot,6a-epoxyandrostane.

42. A process for the production of 61z-fiuoroprogesterone whichcomprises: reacting 65-fluoroprogesterone with a strong mineral acid toobtain 61x-fiuoroprogesterone.

43. A process for the production of 6m-fiuoroprogesterone whichcomprises: reacting 65-fluoroprogesterone with hydrochloric acid toobtain fia-fluoroprogesterone.

44. 6-fluoro-17a-hydroxyprogesterone.

45. 65-fiuoro-l71z-hydroxyprogesterone.

46. 61z-fluoro-l7o1-hydroxyprogesterone.

47. 6-fluoro 171x hydroxyprogesterone 17 acylate, wherein the acyl groupis of a hydrocarbon carboxylic acid containing from one to twelve carbonatoms, inelusive.

48. Lower fatty acid esters of 6-fill01'0-171x-hYdI'OXY- progesterone.

49. 61x-fiuoro-l71z-hydroxyprogesterone 17-acetate.

50. 65-fluoro-171z-hydroxyprogesterone 17-acetate.

51. 5,6 oxido 171x hydroxypregnane 3,20 dione 17-acylate, 3-alkyleneketal wherein the acyl group is of a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms and wherein the alkyleneradical contains not more than eight carbon atoms, inclusive, and theattaching oxygen to carbon bonds are separated by a chain of at leasttwo and not more than three carbon atoms.

52. 51:1,6111-oxido 17 hydroxypregnane 3,20 dione l7-acetate S-ethyleneketal.

53. 5111,1701 dihydroxy 65 fluoropregnane 3,20- dione 17-acylate,3-alkylene ketal wherein the acyl group is of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms and wherein the alkyleneredical contains not more than eight carbon atoms, inclusive, and theattaching oxygen to carbon bonds are separated by a chain of at leasttwo and not more than three carbon atoms.

54. 5111,1701 dihydroxy 65 fiuoro-pregnane 3,20- dione 17-acetate,3-ethylene ketal.

55. 5121,1701 dihydroxy 65 fluoropregnane 3,20- dione 17-acylate whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

56. 5111,1711 dihydroxy 65 fluoropregnane 3, 20- dione 17-acetate.

57. A process for the production of 6-fiuoro171xhydroxyprogesterone17-acylate which comprises: dehy drating a 50:, 17e1-dihydroxy 65fiuropregnane-3,20- dione 17-acylate with a compound selected fromstrong acids and alkali metal hydroxides to obtain6-flUO1'O-l7ahydroxyprogesterone 17-acy1ate.

58. A process for the production of 61 1-fluoro-17o1-hydroxyprogesterone 17-acetate which comprises: dehydrating51x,171z-dihydroxy-65-fluoropregnane 3,20-dione 17-acetate with a strongmineral acid to obtain Get-fluorol71x-hydroxyprogesterone 17-acylate.

59. A process for the production of 6a-fluoro-171xhydroxyprogesterone17-acetate which comprises: dehydrating 5111,1711 dihydroxy 65fluoropregnane 3,20- dione 17-acetate with dilute alkali at atemperature between zero and forty degrees centigrade to obtain 65-fluoro 171x hydroxyprogesterone 17 acetate, and isomerizing the thusobtained 65-fluoro-171x-hydroxyprogesterone 17-acetate with a strongmineral acid to obtain 61 1-fluoro-l71z-hydroxyprogesterone 17-acetate.

60. 6-fluoro-175-hydroxy-4-androsten-3-one.

61. 61 1-fluoro-175-hydroxy-4androsten-3-one.

62. 65-fluoro-175-hydroxy-4-androsten-3-onc.

63. 65 fluoro 35,511,171: trihydroxypregnan one 17-acylate, wherein theacyl group is of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

64. -fiuoro 35,511,1701 trihydroxypregnan 20 one 17-acetate.

65. 65-fiuoro 35,501,1701 trihydroxypregnan 20-one 3,17-diacylate,wherein the acyl radical is of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

66. 65 fluoro 35,511,171: trihydroxypregnan 20- one 3,17-diacetate.

67. 5,6 oxido 35,1701 dihydroxy-pregnan 20 one 3,17 diacylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

68. 511,611 oxido 35,1701 dihydroxypregnan 20- one 3,17-diacylate,wherein the acyl group is of a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive.

69. 55,65 oxido 35,1711 dihydroxypregnan 20-one 3,17-diacylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

70. 5111,6111 oxido 35,1711 dihydroxypregnan 20- one 3,17-diacetate.

71. 55,65 oxido-35,171 1 dihydroXypregnan 20-one 3,17-diacetate.

72. 5,6 oxido 35,1701 dihydroxypregnan 20 one 17-acylate, wherein theacyl group is of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

73. 501,611 oxido 35,1711 dihydroxypregnan 20-one 17-acylate, whereinthe acyl group is of a hydrocarbon carboxylic acid containing from oneto twelve carbon atoms, inclusive.

74. 55,65 oXido 35,1711 dihydroxypregnan 20-one 17-acylate, wherein theacyl group is of a hydrocarbon carboxylic acid containing from one totwelve carbon atoms, inclusive.

75. 511,611 oxido 35,1701 dihydroxypregnan 20-one l7-acetate.

76. 55,65 oxido 35,1701 dihydroxypregnan 20-one 17-acetate.

77. 6-fluoro-A -androstene-3,17-dione.

78. 6a-fiuoro-A -androstene-3,l7-dione. 79. 65-fluoro-A-androstene-3,17-dione.

References Cited UNITED STATES PATENTS 2,838,490 6/1958 Babcock et al260239.5 2,838,492 6/1958 Pederson et al. 260-239.5 2,838,496 6/1958Babcock et al. 260-239.55 2,838,497 6/1958 Spero et al. 260-239.552,838,500 6/1958 Campbell et al. 260239.55 2,838,528 6/1958 Campbell etal. 260-3973 2,838,531 6/1958 Babcock et a1. 260397.4

OTHER REFERENCES Iunkman: Arch. Exper. Path. Pharmakol Bd (1954) pp.244-253 relied on.

ELBERT L. ROBERTS, Primary Examiner.

US. Cl. X.R.

U.S. DEPARTMENT OF COMMERCE PATENT OFFICE Washington, 0.0. 20231 UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,438 978April 15 1 Howard J. Ringold et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below Column 26cancel lines 20 to 23 i 26 27 36 to 39 in their entireties comprisingclaims 69, 7l, 74 and 76 iinz "70." should read 69 1' 1ne 28 "72 sh llinezfl, "'73 should read 71.

line 40 7? ouldq e Shoul ,dline 44 "77 should read 73 line 45 "78 rea 7411ne 46 "79 should read 7S i1 the headin to the shoul ea 7S cfifig f11ne "79 Claims" Signed and sealed this 12th day of August 1969 (SEAL)Attest:

WILLIAM E. SCHUYLER,

Edward M. Fletcher, Jr.

Commissioner of Pat Attesting Officer

51. 5,6-OXIDO-17A-HYDROXYPREGNANE-3,20-DIONE 1M-ACYLATE, 3-ALKYLENEKETAL WHEREIN THE ACYL GROUP IS OF A GYDROCARBON CARBOXYLIC ACIDCONTAINING FROM ONE TO TWELVE CARBON ATOMS AND WHEREIN THE ALKYLENERADICAL CONTAINS NOT MORE THAN EIGHT CARBON ATOMS, INCLUSIVE, AND THEATTACHING OXYGEN TO CARBON BONDS ARE SEPARATED BY A CHAIN OF AT LEASTTWO AND NOT MORE THAN THREE CARBON ATOMS.